EFFECTS OF THE 3-HYDROXY-3-METHYLGLUTARYL-COA REDUCTASE INHIBITORS, ATORVASTATIN AND SIMVASTATIN, ON THE EXPRESSION OF ENDOTHELIN-1 AND ENDOTHELIAL NITRIC-OXIDE SYNTHASE IN VASCULAR ENDOTHELIAL-CELLS

Endothelial dysfunction associated with atherosclerosis has been attri buted to alterations in the L-arginine-nitric oxide (NO)-cGMP pathway or to an excess of endothelin-l (ET-I). The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have been shown to ameliora te endothelial function. However, the physiological basis of this obse rvation is largely unknown. We investigated the effects of Atorvastati n and Simvastatin on the pre-proET-1 mRNA expression and ET-1 synthesi s and on the endothelial NO synthase (eNOS) transcript and protein lev els in bovine aortic endothelial cells. These agents inhibited pre-pro ET-1 mRNA expression in a concentration- and time-dependent fashion (6 0-70% maximum inhibition) and reduced immunoreactive ET-1 levels (25-5 0%). This inhibitory effect was maintained in the presence of oxidized LDL (1-50 mu g/ml). No significant modification of pre-proET-1 mRNA h alf-life was observed. In addition, mevalonate, but not cholesterol, r eversed the statin-mediated decrease of pre-proET-1 mRNA levels. eNOS mRNA expression was reduced by oxidized LDL in a dose-dependent fashio n (up to 57% inhibition), whereas native LDL had no effect. Statins we re able so prevent the inhibitory action exerted by oxidized LDL on eN OS mRNA and protein levels. Hence, these drugs might influence vascula r tone by modulating the expression of endothelial vasoactive factors.